Pharmaceutical tablet system that floats on gastric fluid for multipulse release of active substance, and respective processes of producing same and a cup-shaped envelope of same

ABSTRACT

A tablet system for prolonged floating in or on gastric fluid for releasing therein pharmaceutically active substances in an alternate succession of substance release and no-release periods is made up of a multilayered core placed in a cup-shaped envelope. The core is made up of release layers and no-release layers devoid of pharmaceutically active substance, superposed in alternate succession. The cup-shaped envelope covers bottom and side surfaces of the core while leaving exposed an upper surface of the core. The cup-shaped envelope provides for buoyancy by being formed of a compression-sintered mixture comprising hydrophobic material and inert powdered filler. The hydrophobic material is composed of fatty and/or waxy material capable of being sintered by compression and whose bulk density is lower than gastric fluid density. The powdered filler has a loose powder density that is lower than gastric fluid density.

CROSS REFERENCE TO PRIOR APPLICATIONS

Applicant hereby claims foreign priority under 35 U.S.C. §119 fromPCT/IB02/00959 filed 30 Mar. 2002, and European Patent Application No.01108252.6 filed 31 Mar. 2001, the disclosures of which are hereinincorporated by reference.

TECHNICAL FIELD OF THE INVENTION

This invention concerns a pharmaceutical tablet system capable ofprolonged floating in or on gastric fluid for releasing therein one ormore pharmaceutically active substances in the course of an alternatesuccession of periods of substance release and no-release, saidalternate succession including at least two periods of substance releaseseparated by one period of no-release i.e. of latency. This inventionalso concerns a process of producing said pharmaceutical tablet systemand a process of producing a cup-shaped envelope of said pharmaceuticaltablet system.

BACKGROUND ART

For an overall view of the field of the art to which the inventionpertains, reference may be made for instance to Moës A. J.,“Gastroretentive Dosage Forms”, Critical Reviews in Therapeutic DrugCarrier Systems 10(2):143-195 (1993), and also to Singh B. N. et al.,“Floating drug delivery systems: an approach to oral controlled drugdelivery via gastric retention”, Journal of Controlled Release63(3):35-259 (2000).

Pharmaceutical tablet systems capable of prolonged floating in or ongastric fluid e.g. so as to have a long time of residence in a patient'sstomach for releasing therein a pharmaceutically active substance insustained manner are known in the art. Generally, pharmaceutical formshaving a long time of residence in a patient's stomach are of greatinterest, not only because they allow a local treatment of the patient'sstomach wall and more particularly of the gastric mucous membrane, butalso and above all because they allow to release active substance in thevicinity of the patient's duodenum, which is a very favourable locationof the gastro-intestinal tract where a great many active substances arebest absorbed.

There are several approaches for bringing about a prolonged time ofresidence in the stomach.

A tablet system can be formulated so as to adhere to the gastric mucousmembrane (cf. for instance U.S. Pat. No. 5,213,794, U.S. Pat. No.5,571,533, WO-A-93/24124, WO-A-98/42311, WO-A-98/52547). A majordrawback of such adhering systems resides in the difficulty of bringingabout that they reliably adhere and remain adherent to the gastricmucous membrane, for the latter is continually undergoing changes andreplacement processes and is also subject to the peristalsis i.e. tostrong contractions that take place at the stomach wall. In respect ofadherence to the gastric mucous membrane no helpful knowledge can bederived from currently used pharmaceutical forms designed to adhere e.g.onto nasal or buccal surfaces, because such forms need to be pressedonto said surfaces at application time, which pressing is not possibleonto a patient's gastric mucous membrane, to say nothing of the hazardof the forms getting stuck in the patient's esophagus.

A tablet system can also be formulated to have a high apparent densitythat, following ingestion, will cause the system to settle in thestomach at the lower portion of the antrum (cf. for instance U.S. Pat.Nos. 4,193,985, 5,374,430). However, the movement of substancescontained in the stomach towards the lower portion of the antrumparticipates in the natural sequence of events related to gastricdischarge and hence, pharmaceutical forms formulated so as to settle inthe antrum are likely to pass the patient's pylorus either with thebolus (during the digestion process) or together with undigested debris(in the time interval between two successive digestion processes). Thus,to secure the gastroretention of systems formulated so as to have a highapparent density, such systems must additionally be given someproperties that will promote the gastroretention, which will raise againthe problems already discussed above. Indeed, in EP-A-526862 a granulateis disclosed that not only has a high density but also is givenmuco-adhesive properties.

A tablet system can also be formulated so as to grow in the stomach,following ingestion, to a size large enough to hinder the system frompassing the patient's pylorus even when the latter is open. A great manyof these systems are either folded at ingestion time and made to unfoldand open out in the stomach following ingestion (cf. for instanceEP-A-202159, U.S. Pat. Nos. 4,735,804, 4,758,436, 4,767,627, 5,002,772)or they are made to swell in the stomach following ingestion, forexample as a result of gelling (cf. for instance U.S. Pat. Nos.4,434,153, 5,651,985) or carbon dioxide emission (cf. for instance U.S.Pat. No. 4,996,058, WO-A-98/31341). However, systems formulated to swellcould easily pass the patient's pylorus during the latency period thatruns from ingestion time until the system has grown to a sufficient sizefor the gastroretention mechanism to become effective. On the otherhand, systems formulated to unfold and open out in the stomach mightwell be retained permanently in the stomach or even in the esophagus,due to early activation of the deployment mechanism. Each of suchfailure cases will cause severe secondary effects.

A tablet system can also be formulated with agents that delay or slowdown the transit through the stomach, such as lipid-based vehicles (forinstance, fatty acids) or depressors of the central nervous system (forinstance, serotonine antagonists). These agents bring about a reductionof the stomach motility, which in turn slows down the gastric discharge.Such a way of bringing about gastroretention is most often used inassociation with other ways (cf. for instance WO-A-97/47285). However,as systems that bring about a reduction of the stomach motilityinterfere with the whole mechanism of gastric discharge, they are likelyto cause digestion problems or worsen them, if already existing.Furthermore, the use of a serotonine antagonist has to comply withpertaining health and drug regulations.

Hence, all known tablet systems of the above mentioned types must bedeemed unreliable in respect of providing a prolonged time of residencein the stomach and therefore, they all are unsuitable for providingreliably an alternate succession of periods of substance release andno-release with at least two periods of substance release separated byone period of no-release e.g. when structured in accordance with theteaching of EP-A-788790.

A tablet system can also be formulated to float on the content of thestomach.

The buoyancy of such a tablet system may be provided by means of aninitially dense matrix that undergoes gelling in the stomach followingingestion, which causes the matrix to swell and hence, reduces itsdensity (cf. for instance GB-A-1546448, U.S. Pat. Nos. 4,126,672,4,140,755, 4,167,558, 5,169,639, 5,360,793, WO-A-96/29054); or thebuoyancy of such a tablet system may be provided by means of a film orcoating that undergoes carbon dioxide emission in the stomach followingingestion, which causes the film or coating to foam (an effect that maybe understood as a special type of swelling) and hence, reduces itsdensity (cf. for instance U.S. Pat. Nos. 4,101,650, 4,844,905,WO-A-98/47506); or the buoyancy of such a tablet system may be obtainedby providing it right from the start (i.e. before ingestion) with adensity that is sufficiently low to keep the tablet system floating inthe stomach following ingestion (cf. for instance JP-A-3-101615, U.S.Pat. Nos. 3,976,764, 4,702,918, 4,814,178, 4,814,179, 5,198,229,5,232,704, 5,288,506, 5,626,876).

Besides the fact that some of these tablet systems formulated to floaton the content of the stomach may have their own severe drawbacks, allthese systems (with the single exception of the above-mentioned U.S.Pat. No. 4,140,755) only bring about a single period of release ofactive substance (irrespective of the fact that the active substance mayactually consist of a mixture of active compounds). As to the systemdisclosed in the above-mentioned U.S. Pat. No. 4,140,755, this lattersystem can only bring about a single immediate release of activesubstance followed by a single prolonged release of the same activesubstance.

Thus, none of the above-mentioned tablet systems formulated to float onthe content of the stomach is capable of providing reliably a“multipulse release” consisting of an alternate succession of periods ofsubstance release and no-release, which alternate succession wouldinclude at least two periods of substance release separated by oneperiod of no-release.

Yet, such a multipulse release capability is highly desirable in atablet system formulated to float on the content of the stomach, for itwould allow a patient to take one single drug unit form to produce adrug plasma level scheme that can only result at present times fromadministering to the patient two or more standard-type fast-release drugunit forms to be taken in succession at respective predefined timeinstants separated by respective predefined latency or waiting periods.

Pharmaceutical tablet systems having a multipulse release capability areknown in the art.

One type of a pharmaceutical tablet system having a multipulse releasecapability is known for instance from EP-A-1074249 and is constructed asa multilayered body arranged concentric about a core, which core isfully enclosed within layers that fully enclose one another insuccession. The core is the last part of the tablet system that willdisappear by dissolution or digestion in gastric fluid or by gastricdischarge and hence, to confer prolonged buoyancy to such a tabletsystem and prevent any early sinking or discharge thereof, at least thecore should be formed of lightweight materials. Moreover, inconsideration of the possible gastric discharge of the core, a reliableadministration can only be attained with a core devoid of any activesubstance that participates in the desired multipulse releasecapability, which is not an economical construction because of thenecessarily large size of the core.

Another type of a pharmaceutical tablet system having a multipulserelease capability is known for instance from WO-A-91/04015, EP-A-631775or EP-A-788790 and is, basically, made up of planar layers superposed ina stack that is enclosed within an envelope so as to leave at least oneouter face of an outer layer of the stack uncovered and unprotected bythe envelope. In particular, there is disclosed in EP-A-788790 apharmaceutical tablet system to be administered by the oral route forreleasing one or more pharmaceutically active substances in the courseof an alternate succession of periods of substance release andno-release, said alternate succession including at least two periods ofsubstance release separated by one period of no-release. This type ofpharmaceutical tablet system is neither intended nor provided forprolonged floating in or on gastric fluid in a patient's stomach.

To nevertheless confer buoyancy to this type of pharmaceutical tabletsystem, it may be envisaged to use lightweight materials to form theenvelope, and this may be expected to be easiest in a tablet systemhaving a cup-shaped envelope and a multilayered core placed therein, asdisclosed in EP-A-788790. The cup-shaped envelope is the last part ofthe tablet system that will disappear by dissolution or digestion ingastric fluid or by gastric discharge and hence, to confer prolongedbuoyancy to such a tablet system and prevent any early sinking ordischarge thereof, at least the cup-shaped envelope should be formed oflightweight materials. Moreover, in consideration of the possiblegastric discharge of the cup-shaped envelope, a reliable multipulserelease can only be attained with a cup-shaped envelope devoid of anyactive substance that participates in the desired multipulse releasecapability.

Lightweight materials, the use of which may be envisaged inpharmaceutical tablet systems of the above-mentioned type having amultipulse release capability, are known e.g. from the prior artmentioned above. Also, fatty and/or waxy lightweight materials have beenused to obtain tablet systems having a low density, for instanceaccording to JP-A-1-016715 that discloses a system having a fatty coremade up of fats and oils of density _(—)0.98 and at least one coatinglayer that contains active substance.

However, these known lightweight materials will not withstand aprolonged floating in or on gastric fluid, as some will dissolve in thegastric fluid, which will cause a progressive loss of buoyancy andsubsequent gastric discharge of the tablet system, and others willexperience a change of volume e.g. due to gelling that in turn willentail changes of shape allowing the core to eventually become detachedfrom the cup-shaped envelope: in either case the multipulse releasecharacteristics will be unreliable. In a pharmaceutical tablet system ofthe type mentioned above made up of a stack of superposed layers that isenclosed within an envelope with an outer layer of the stack having anouter face left uncovered and unprotected by the envelope, any poorcontact and attachment between the stack of layers and the envelope willallow gastric fluid to infiltrate the system, causing fragility of thetablet system as well as undesirable variations more particularly of thein vivo release rate of the active substance from the innermost i.e.lowermost layer of the stack, producing the so-called “dose dumping”. Inthe particular tablet system having a cup-shaped envelope and amultilayered core placed therein (as disclosed in EP-A-788790) thecaused fragility of the tablet system may even allow the core to detachfrom the cup-shaped envelope.

Also, fats and oils that are currently used (alone or in mixture) inpharmaceutical tablet systems to confer them a density that is lowerthan unity do not allow tablet production using a compression step ofthe kind performed in any currently used type of tablet compressionapparatus, because of feeding and sticking problems: such fats and oils(whether taken as powders or liquids) have flow properties that do notallow to reliably and evenly fill the press moulds, and during thecompression step they stick to the moulding plug and die, impairing thecompression efficiency and uniformity.

SUMMARY OF THE INVENTION

Thus, it is an object of the present invention to make available apharmaceutical tablet system capable of prolonged floating in or ongastric fluid under conditions that are safe for a patient to whom saidpharmaceutical tablet system is being administered, for releasing in thepatient's stomach one or more pharmaceutically active substances in thecourse of an alternate succession of periods of substance release andno-release, said alternate succession including at least two periods ofsubstance release separated by one period of no-release i.e. of latency,and which pharmaceutical tablet system does not have the drawbacks ofthe floating systems of the prior art mentioned above and in particular,should remain floating in or on the gastric fluid in a patient's stomachuntil the totality of the active substance contained in thepharmaceutical tablet system has been released, irrespective of the factthat said active substance may actually consist of a mixture of activecompounds.

To attain this object, according to the present invention there isprovided a pharmaceutical tablet system capable of prolonged floating inor on gastric fluid for releasing therein one or more pharmaceuticallyactive substances in the course of an alternate succession of periods ofsubstance release and no-release, said alternate succession including atleast two periods of substance release separated by one period ofno-release, whereby:

the tablet system is made up of a multilayered core placed in acup-shaped envelope;

the core is made up of release and no-release layers superposed inalternate succession to form a pile of layers that includes at least tworelease layers flanking an intermediate no-release layer, each releaselayer being composed of pharmaceutically acceptable excipient and/orcarrier having admixed thereto at least one of said pharmaceuticallyactive substances, each no-release layer being composed ofpharmaceutically acceptable excipient and/or carrier devoid of saidpharmaceutically active substance;

the cup-shaped envelope covers a bottom surface and side surfaces of thecore placed therein while leaving exposed an upper surface of the core;

the cup-shaped envelope provides for buoyancy of the pharmaceuticaltablet system with respect to gastric fluid by being formed of acompression-sintered mixture that comprises pharmaceutically acceptablehydrophobic material and pharmaceutically acceptable inert powderedfiller;

the hydrophobic material is composed of fatty and/or waxy materialcapable of being sintered by compression and whose bulk density is lowerthan gastric fluid density; and

the powdered filler having a loose powder density that is lower thangastric fluid density.

Preferably, in a pharmaceutical tablet system according to the presentinvention the voids may be interstices between grains of the powderedfiller, and more preferably, may be generally sealed off from each otherby virtue of the hydrophobic material. Also preferably, the voids may bemicropores included within the hydrophobic material. Also preferably,the mixture, which the cup-shaped envelope is made of, also includes atleast one or more pharmaceutically active agent different from saidsubstances contained in one or more release layers.

A process of producing the above-defined pharmaceutical tablet systeminvolves the steps of coating the powdered filler with the hydrophobicmaterial, preferably by spray-coating performed under vigorous stirring;granulating the resulting coated material; placing a layer of theresulting granulated material into a die; placing a core onto the layerof granulated material within the die; forcing the core into the layerof granulated material within the die, which forcing preferably involvesa compression of the tablet system made up of the cup-shaped envelopehaving the core inserted therein to provide a snug fit between mutuallyfacing bottom and side surfaces of the core and surface portions of thecup-shaped envelope; and removing the resulting tablet system from thedie.

A process of producing a cup-shaped envelope of the above-definedpharmaceutical tablet system involves the steps of coating the powderedfiller with the hydrophobic material, preferably by spray-coatingperformed under vigorous stirring; granulating the resulting coatedmaterial; placing a layer of the resulting granulated material into adie; forming a cup-shaped recess into the layer of granulated materialby forcing a correspondingly shaped body into it within the die; andremoving the resulting cup-shaped envelope from the die.

In the pharmaceutical tablet system of the present invention it is thecup-shaped envelope that provides for buoyancy with respect to gastricfluid. The system is constructed to float on gastric fluid at leastuntil the core will have disappeared completely by dissolution ordigestion in the gastric fluid and/or subsequent gastric discharge,which also means that all of the active substance will have been fullyreleased. Accordingly, a pharmaceutical tablet system of the presentinvention will reliably bring about the desired “multipulse release”defined above, irrespective of the fact that the active substance mayactually consist of a mixture of active compounds, and irrespective ofthe duration of the release or no-release i.e. latency periods.

A great advantage of the pharmaceutical tablet system of the presentinvention is that it allows a patient to take one single drug unit formto reliably produce a drug plasma level scheme equivalent to that whichwould result from the patient's taking in succession two or morestandard-type fast-release drug unit forms at respective predefined timeinstants separated by respective predefined no-release i.e. latency orwaiting periods.

It is particularly advantageous to produce the tablet system by means ofthe preferred process according to the present invention, which processreliably allows to obtain a snug fit between mutually facing bottom andside surfaces of the core and surface portions of the cup-haspedenvelope, which snug fit in turn prevents the core from detaching tooearly from the cup-shaped envelope and hence, allows the tablet systemto provide reliably the desired “multipulse release”.

Moreover, the lightweight material used in the pharmaceutical tabletsystem of the present invention is advantageously well adapted to becompressed in currently used rotary or reciprocating presses withoutgiving rise to any sticking or feeding problems. This finding is quitesurprising in view of the difficulties (e.g. unreliable and irregularfilling of press moulds, sticking to the moulding plug, impairedcompression) that are encountered when fats and oils are used to obtaina low apparent density as taught in the prior art e.g. of JP-A-1-016715quoted above.

Also, inherent to producing the pharmaceutical tablet system of thepresent invention according to the above said process, the lightweightmaterial may advantageously be imparted such appropriate hardness andfriability properties that will allow an easy handling of intermediateand final products during any subsequent operations such as filmcoating, packaging etc.

In the process of producing the pharmaceutical tablet system of theinvention, the combined provision of using of a hydrophobic materialcomposed of fatty and/or waxy material capable of being sintered bycompression, using a powdered filler having a loose powder density thatis lower than gastric fluid density and compressing the cup-shapedenvelope having the core inserted therein is advantageous in that itresults in a snug fit between the core and the cup-shaped envelope. Thissnug fit seals off the core from the gastric fluid except for the outerface of the core and thus, precludes any poor contact and attachmentbetween the core and the cup-hasped envelope. As no gastric fluid isallowed to infiltrate along the interface between the core and thecup-shaped envelope, the risk of early dissolution or degradation of anyother portions of the core than the vicinity if its outer surface isavoided. Such early dissolution would make the no-release or latencyperiod unreliable and/or cause early release of active substance fromlower layers of the core, which in turn would lead e.g. to a sustainedrelease instead of a multipulse release of active substance from thepharmaceutical tablet system.

It is a further advantage of the pharmaceutical tablet system of theinvention that the hydrophobic material composed of fatty and/or waxymaterial is sintered by compression, not by melting. Both the degree ofsintering and the degree of penetration of the hydrophobic material intothe powdered filler can be varied by means of the sintering pressureused, which allows to vary the final properties of the cup-shapedenvelope, including the latter's final porosity and thus, the overallporosity of the system.

It is a still further advantage of the pharmaceutical tablet system ofthe invention that its mechanisms that provide for release andno-release and for buoyancy are independent from each other. This isbecause no hydrocolloids are used to provide for buoyancy with respectto gastric fluid, the tablet system experiences no change of volume, itsbuoyancy is not obtained by any gelling of hydrocolloids, and the activesubstance may be released by other mechanisms that diffusion through agelled body, which latter mechanism usually leads to a sustainedrelease. All the more, hydrocolloids have a gelling speed that, in apatient's gastric fluid, depends on physiological circumstances such ason the patient's stress, the fluid quantity available in the stomach,the instant filling state of the stomach etc., and in the pharmaceuticaltablet system of the invention this is avoided.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an exemplary embodiment of a tablet system accordingto the present invention with a cylindrical tablet viewed in a schematicaxial section;

FIG. 2 illustrates in vitro release characteristics of a tablet systemaccording to FIG. 1 with a composition according to Example 1.

FIG. 3 illustrates in vitro release characteristics of a tablet systemaccording to FIG. 1 with a composition according to Example 2.

FIG. 4 illustrates in vitro release characteristics of a tablet systemaccording to FIG. 1 with a composition according to Example 3.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be explained in closer detail withreference to an exemplary structure of a pharmaceutical tablet system,which structure is of the kind generally known from EP-A-788790. Thisexemplary structure is constructed cylindrical, and an axial sectionthereof is illustrated schematically in FIG. 1.

Generally, the tablet structure illustrated in FIG. 1 comprises a corepartially enclosed within an envelope made of lightweight material thatprovides for buoyancy of the pharmaceutical tablet system with respectto gastric fluid e.g. in a patient's stomach. The core is made up of ofthree planar layers that are superposed sandwich-like in a generallycylindrical stack having a latency layer 2 located intermediate betweenactive layers 1 and 3. Also, the core is snugly enclosed within acup-shaped envelope 4 that is generally shaped as a blin-dend hollowcylinder having an axial cylindrical cavity in which the core i.e. thestack of layers 1, 2 and 3 is snugly accommodated in such manner that anouter face of the outer layer 1 of the stack remains uncovered andunprotected by the envelope 4.

The active layers 1 and 3 each are designed to provide release of one ormore pharmaceutically active substances and thus, they each containactive substance that is, in the present description and by way ofexample, diltiazem HCl. The latency layer 2 is designed devoid of activesubstance so as to provide a period of no-release i.e. of latency.

EXAMPLE 1

1. Preparation of Active Layers

Active layers i.e. layers containing active substance were prepared,each having a weight of 62.50 mg and the following percentagecomposition (by weight):

diltiazem HCl 30.00% lactose (lactose pulvis H2O, 200 Mesh) 59.50% fromPaul Brem AG, Switzerland sodium croscarmellose Ac-Di-Sol^((R)), 5.00%from FMC Corporation, USA polyvinylpyrrolidone Plasdone^((R)) K29-32,4.00% from ISP AG, Switzerland magnesium stearate from Merck, Germany1.00% colloidal silica Aerosil^((R)) 200, 0.50% from Degussa AG, Hanau,Germany Total composition 100.00%

Granulate was prepared in an amount appropriate to allow the productionof 12000 cores of the type described above i.e. of 24000 active layers.

Proper amounts of Diltiazem HCl, lactose, sodium croscarmellose andpolyvinylpyrolidone were placed in a mixer (from Stephan, Switzerland)and mixed therein. Subsequently the homogeneous mixture was wetted withdemineralised water and then further mixed, a process known in the artas a “wet massing” step.

The paste so obtained was dried in a fluidised air bed drier (typeNiro-Aeromatic Strea I, 60° C. inlet air temperature, fromAeromatic-Fielder AG, Switzerland). The resulting dried mass was thensized through a sieve granulator (type Frewitt GLA, from FrewittFabrique de Machines SA, Switzerland) with a sieve of 0.8 mm aperture,which step produced calibrated granulate.

This calibrated granulate was then placed in a cubic mixer (type Erweka,from Mapag Maschinen AG, Switzerland), added with a proper amount ofcolloidal silica, and mixed for 15 min at 12 rpm. Then, a proper amountof magnesium stearate was added, and mixing was continued for 5 min.This mixture was then used for the compression step as described below.

2. Preparation of No-release i.e. Latency Layers

Latency layers i.e. layers devoid of active substance were prepared,each having a weight of 100.00 mg and the following percentagecomposition (by weight):

dibasic calcium phosphate 45.00% from Emcompress^((R)), Mendell, USA)lactose (lactose pulvis H2O, 200 Mesh) 20.00% Lactose Fast Flo^((R)),from Foremost, USA glyceryl behenate Compritol^((R)) 888 ATO, 25.00%from Gattefossé, France polyvinylpyrrolidone Plasdone^((R)) K29-32,8.40% from ISP AG, Switzerland yellow ferric oxide Sicovit^((R)) Yellow10E172, 0.10% from Bascom AG, Switzerland magnesium stearate from Merck,Germany 1.00% colloidal silica Aerosil^((R)) 200, 0.50% from Degussa AG,Hanau, Germany Total composition 100.00%

Granulate was prepared in an amount appropriate to allow the productionof 15000 cores of the type described above i.e. of 15000 latency layers.

Proper amounts of dibasic calcium phosphate, lactose, glyceryl behenate,polyvinylpyrolidone and yellow ferric oxide were placed in a mixer (fromStephan, Switzerland) and mixed therein. The homogeneous mixture wasthen wetted with demineralised water and then further mixed in a “wetmassing” step.

The paste so obtained was dried in a fluidised air bed drier (typeNiro-Aeromatic Strea I, 50° C. inlet air temperature, fromAeromatic-Fielder AG, Switzerland). The resulting dried mass was thensized through a sieve granulator (type Frewitt GLA, from FrewittFabrique de Machines SA, Switzerland) with a sieve of 0.8 mm aperture,which step produced calibrated granulate.

This calibrated granulate was then placed in a cubic mixer (type Erweka,from Mapag Maschinen AG, Switzerland), added with a proper amount ofcolloidal silica, and mixed for 15 min at 12 rpm. Then, a proper amountof magnesium stearate was added, and mixing was continued for 5 min.This mixture was then used for the compression step as described below.

Preparation of Buoyant Material

Buoyant material was prepared, having the following percentagecomposition (by weight):

hydrogenated castor oil Cutina HR^((R)), 70.00% from Impag AG,Switzerland magnesium aluminometasilicate Neusilin UFL^((R)), 12.25%from Gustav Parmentier, Germany microcrystalline cellulose Avicel^((R))pH 101, 12.25% from Selectchemie AG, Switzerland gelatine from Merck,Germany 5.00% magnesium stearate from Merck, Germany 0.50% Totalcomposition 100.00%

In the above composition eventually used for preparing the cup-shapedenvelope, cf. below, the hydrophobic material is hydrogenated castor oiland the inert powdered filler is magnesium aluminometasilicate.

Granulate was prepared in an amount appropriate to allow the productionof 1000 buoyant cup-shaped envelopes each having a weight of 500.00 mgappropriate to enclose 1000 cores so as to manufacture 1000 tablets.

Proper amounts of hydrogenated castor oil, magnesium aluminometasilicateand cellulose microcrystalline were placed in a high shear mixer (typeNiro-Fielder PP1, from Aeromatic-Fielder AG, Switzerland). Thehomogeneous mixture was then wetted with a gelatine solution made up ofgelatine previously dissolved in demineralised water and then furthermixed in a “wet massing” step.

The paste so obtained was dried in a fluidised air bed drier (typeNiro-Aeromatic Strea I, 50° C. inlet air temperature, fromAeromatic-Fielder AG, Switzerland). The resulting dried mass was thensized through a sieve granulator (type Frewitt GLA, from FrewittFabrique de Machines SA, Switzerland) with a sieve of 0.8 mm aperture,which step produced calibrated granulate.

This calibrated granulate was then placed in a cubic mixer (type Erweka,from Mapag Maschinen AG, Switzerland), added with a proper amount ofcolloidal silica, and mixed for 10 min at 12 rpm. This mixture was thenused for the compression step as described below.

Preparation of Cores

Cores were prepared by means of a rotating three layer press (typeManesty LP39, from Keyser Mackay, Switzerland) equipped with circularconvex punches having a diameter of 7.0 mm, operating on the granulatesprepared as described above with bulk active layer material in the firstand third filling hoppers and bulk latency layer material in the secondfilling hopper.

Application of Buoyancy Conferring Layers Onto Cores

The cores previously prepared as described above were press-coated withthe buoyant material prepared as described above by means of a singlepunch machine (type Korsch, from Korsch Maschinenfabrik, Germany)equipped with dies and circular convex punches having a diameter of 13.0mm. The die was filled with an exact quantity of the buoyant materialand then the core was placed manually in the die and centred.Subsequently, the compression step was then performed.

The resulting tablets had a thickness of 7.10 mm and a hardness of about75N.

Results

To determine the in vitro release characteristics of the tabletsdescribed above, a standard equipment was used as defined and describedin United States Pharmacopoeia USP XXIII, chapter 711, page 1792,paragraph “Apparatus 2”. This equipment had a stirring paddle comprisedof a blade and a shaft and was operated at 100 rpm. Dissolution wasinvestigated at 37° C. in 600 ml of a dissolution medium made up of 0.1Macetate buffer of pH 4.5. The release of the active substance (diltiazemHCl) was monitored by UV spectrophotometry at 278 nm for 6 individualsamples and additionally, as a reference, for the dissolution mediumtaken alone i.e. devoid of any tablet material.

The results are illustrated in FIG. 2 as respective time profilediagrams for the 6 tablet samples and the reference. The referencediagram showed that the dissolution medium taken alone i.e. devoid ofany tablet material did not bias the results or generate any artifacts.The in vitro release characteristics of all 6 tablets appeared to form awell grouped family that was well separated from the referencecharacteristic which appeared in the lowest part of the diagram.

In each instance, the following was observed on the in vitro releasecharacteristics:

The first release of active substance takes place within a releaseperiod of less than a one hour duration.

The no-release period appears as a well-defined time interval observedbetween the end of the first release and the start of the secondrelease, having a duration of more than 8 hours in each instance.

The second release of active substance is observed to produce acontrolled release.

During the course of the dissolution the tablet system was monitoredvisually and observed to remain buoyant for the whole duration of theexperiment.

EXAMPLE 2

1. Preparation of Active Layers

Active layers i.e. layers containing active substance were prepared,each having a weight of 62.50 mg and the following percentagecomposition (by weight):

diltiazem HCl 30.00% lactose (lactose pulvis H2O, 200 Mesh) 34.50% fromPaul Brem AG, Switzerland sodium croscarmellose Ac-Di-Sol^((R)), 5.00%from FMC Corporation, USA sodium hydrogen carbonate 15.00% from CFS,Switzerland polyvinylpyrrolidone Plasdone^((R)) K29-32, 4.00% from ISPAG, Switzerland citric acid from Merck, Germany 10.00% magnesiumstearate from Merck, Germany 1.00% colloidal silica Aerosil^((R)) 200,0.50% from Degussa AG, Hanau, Germany Total composition 100.00%

Granulate was prepared in an amount appropriate to allow the productionof 11000 cores of the type described above i.e. of 22000 active layers,using the same procedure as described above under Example 1 applied toproper amounts, first of diltiazem HCl, lactose, sodium croscarmellose,sodium hydrogen carbonate and polyvinylpyrolidone, and then of colloidalsilica and citric acid, placed in the respective mixer.

Preparation of No-release i.e. Latency Layers

Latency layers i.e. layers devoid of active substance were prepared,each having a weight of 70.00 mg and the following percentagecomposition (by weight):

dibasic calcium phosphate 37.50% from Emcompress^((R)), Mendell, USA)lactose (lactose pulvis H2O, 200 Mesh) 33.34% Lactose Fast Flo^((R)),from Foremost, USA glyceryl behenate Compritol^((R)) 888 ATO, 20.83%from Gattefossé, France polyvinylpyrrolidone Plasdone^((R)) K29-32,7.00% from ISP AG, Switzerland yellow ferric oxide Sicovit^((R)) Yellow10E172, 0.08% from Bascom AG, Switzerland magnesium stearate from Merck,Germany 0.83% colloidal silica Aerosil^((R)) 200, 0.42% from Degussa AG,Hanau, Germany Total composition 100.00%

Granulate was prepared in an amount appropriate to allow the productionof 2150 cores of the type described above i.e. of 2150 latency layers,using the same procedure as described above under Example 1 applied toproper amounts, first of dibasic calcium phosphate, lactose, glycerylbehenate, polyvinylpyrolidone and yellow ferric oxide, and then ofcolloidal silica, placed in the respective mixer.

Preparation of Buoyant Material

Buoyant material was prepared, having the following percentagecomposition (by weight):

hydrogenated castor oil Cutina HR^((R)), 70.00% from Impag AG,Switzerland magnesium aluminometasilicate Neusilin UFL^((R)), 22.00%from Gustav Parmentier, Germany gelatine from Merck, Germany 5.00%hydrogenated cottonseed oil from Merck, Germany 3.00% Total composition100.00%

In the above composition eventually used for preparing the cup-shapedenvelope, cf. below, the hydrophobic material is a mixture ofhydrogenated castor oil and hydrogenated cottonseed oil, and the inertpowdered filler is magnesium aluminometasilicate.

Granulate was prepared in an amount appropriate to allow the productionof 300 buoyancy conferring cup-hasped envelopes each having a weight of500.00 mg appropriate to enclose 300 cores so as to manufacture 300tablets, using the same procedure as described above under Example 1applied to proper amounts, first of hydrogenated castor oil andmagnesium aluminometasilicate, and then of colloidal silica, placed inthe respective mixer.

4. Preparation of Cores

Cores were prepared by means of a single punch machine (type Korsch,from Korsch Maschinenfabrik, Germany) equipped with dies and circularflat punches having a diameter of 7.0 mm. The die was filled with exactquantities of the granulates prepared above, each corresponding to therespective layers. The compression step resulted in cores having athickness of 3.90 mm and a hardness of about 50N.

5. Application of Buoyancy Conferring Cup-shaped envelopes onto cores

The cores previously prepared as described above were press-coated withthe buoyant material prepared as described above, using the sameprocedure as described above under Example 1. The compression stepresulted in tablets having a thickness of 7.10 mm and a hardness ofabout 75N.

6. Results

The in vitro release characteristics of the tablets described above weredetermined, using the same procedure as described above under Example 1except for monitoring the release of the active substance (diltiazemHCl) by UV spectrophotometry at 240 nm for 5 individual samples.

The results are illustrated in FIG. 3 as respective time profilediagrams for the 5 tablet samples. The in vitro release characteristicsof all 5 tablets appeared to form a well grouped family.

In each instance, the following was observed on the in vitro releasecharacteristics:

The first release of active substance takes place within a releaseperiod of less than a one hour duration.

The no-release period appears as a well-defined time interval observedbetween the end of the first release and the start of the secondrelease, having a duration of more than 4 hours in each instance.

The second release of active substance takes place within a releaseperiod of less than a one hour duration.

During the course of the dissolution the tablet system was monitoredvisually and observed to remain buoyant for the whole duration of theexperiment, which duration largely exceeded the time required to releasethe tablet system's whole content of active substance.

EXAMPLE 3

1. Preparation of Active Layers

Active layers i.e. layers containing active substance were prepared,using the same procedure as described above under Example 1.

2. Preparation of No-release i.e. Latency Layers

Latency layers i.e. layers devoid of active substance were prepared,each having a weight of 100.00 mg and the following percentagecomposition (by weight):

dibasic calcium phosphate 43.00% from Emcompress^((R)), Mendell, USA)lactose (lactose pulvis H2O, 200 Mesh) 30.00% Lactose Fast Flo^((R)),from Foremost, USA sodium croscarmellose Ac-Di-Sol^((R)), 2.00% from FMCCorporation, USA glyceryl behenate Compritol^((R)) 888 ATO, 15.00% fromGattefossé, France polyvinylpyrrolidone Plasdone^((R)) K29-32, 8.40%from ISP AG, Switzerland yellow ferric oxide Sicovit^((R)) Yellow10E172, 0.10% from Bascom AG, Switzerland magnesium stearate from Merck,Germany 1.00% colloidal silica Aerosil^((R)) 200, 0.50% from Degussa AG,Hanau, Germany Total composition 100.00%

Granulate was prepared in an amount appropriate to allow the productionof 1500 cores of the type described above i.e. of 1500 latency layers,using the same procedure as described above under Example 1 applied toproper amounts, first of dibasic calcium phosphate, lactose, sodiumcroscarmellose, glyceryl behenate, polyvinylpyrolidone and yellow ferricoxide, and then of magnesium stearate and colloidal silica, placed inthe respective mixer.

3. Preparation of Buoyant Material

Buoyant material was prepared, using the same procedure as describedabove under Example 1, leading to the same composition eventually usedfor preparing the cup-shaped envelope, cf. below, in which thehydrophobic material is hydrogenated castor oil and the inert powderedfiller is magnesium aluminometasilicate.

4. Preparation of Cores

Cores were prepared, using the same procedure as described above underExample 2, to result in cores having a thickness of 4.25 mm and ahardness of about 50N.

5. Application of Buoyancy Conferring Cup-shaped Envelopes Onto Cores

The cores previously prepared as described above were press-coated withthe buoyant material prepared as described above, using the sameprocedure as described above under Example 1. The compression stepresulted in tablets having a thickness of 7.05 mm and a hardness ofabout 105N.

6. Results

The in vitro release characteristics of the tablets described above weredetermined, using the same procedure as described above under Example 2except for monitoring the release of the active substance (diltiazemHCl) for 6 individual samples.

The results are illustrated in FIG. 4 as respective time profilediagrams for the 6 tablet samples. The in vitro release characteristicsof all 6 tablets appeared to form a well grouped family.

In each instance, the following was observed on the in vitro releasecharacteristics:

The first release of active substance takes place within a releaseperiod of less than a one hour duration.

The no-release period appears as a well-defined time interval observedbetween the end of the first release and the start of the secondrelease, having a duration of more than 2 hours in each instance.

The second release of active substance takes place within a releaseperiod of less than a one hour duration.

During the course of the dissolution the tablet system was monitoredvisually and observed to remain buoyant for the whole duration of theexperiment, which duration largely exceeded the time required to releasethe tablet system's whole content of active substance.

SUMMARY OF EXPERIMENTAL RESULTS

In each instance of the Examples, in the composition eventually used forpreparing the cup-shaped envelope the inert powdered filler is magnesiumaluminometasilicate and the hydrophobic material is hydrogenated castoroil (in Example 1 and Example 3) or a mixture of hydrogenated castor oiland hydrogenated cottonseed oil (in Example 2).

In each instance and for all three Examples, the first release of activesubstance takes place within a release period of less than a one hourduration.

In each instance, the no-release period appears to be a well-definedtime interval observed between the end of the first release and thestart of the second release, having a duration of more than 8 hours ineach instance of Example 1, 4 hours in each instance of Example 2, and 2hours in each instance of Example 3.

In each instance, the second release of active substance is observed toproduce a controlled release having a prolonged duration (sustainedrelease) in each instance of Example 1, and in contrast a duration ofless than one hour in each instance of Example 2 and Example 3.

During the course of the dissolution the tablet system was monitoredvisually and observed to remain buoyant for the whole duration of theexperiment, which duration largely exceeded the time required to releasethe tablet system's whole content of active substance in each instanceof Example 2 and Example 3.

1. A pharmaceutical tablet system capable of prolonged floating in or ongastric fluid for releasing therein one or more pharmaceutically activesubstances in the course of an alternate succession of periods ofsubstance release and no-release, said alternate succession having atleast two periods of substance release separated by one period ofno-release, whereby the tablet system is made up of a multilayered coreplaced in a cup-shaped envelope, the core is made up of release andno-release layers superposed in alternate succession to form a pile oflayers that has at least two release layers flanking an intermediateno-release layer, each release layer being composed of pharmaceuticallyacceptable excipient and/or carrier having admixed thereto at least oneof said pharmaceutically active substances, each no-release layer beingcomposed of pharmaceutically acceptable excipient and/or carrier devoidof said pharmaceutically active substance, the cup-shaped envelopecovers a bottom surface and side surfaces of the core placed thereinwhile leaving exposed an upper surface of the core, characterized inthat the cup-shaped envelope provides for buoyancy of the pharmaceuticaltablet system with respect to gastric fluid by being formed of acompression-sintered mixture with voids, the mixture being comprised bybuoyancy-providing materials in the form of a pharmaceuticallyacceptable hydrophobic material and a pharmaceutically acceptable inertpowdered filler, the hydrophobic material being composed of fatty and/orwaxy material capable of being sintered by compression and whose bulkdensity is lower than gastric fluid density, and the powdered fillerhaving a loose powder density that is lower than gastric fluid density,the powdered filler consisting of magnesium aluminometasilicate; and thebuoyancy-providing materials of the cup-shaped envelope beingincorporated in the finished pharmaceutical tablet system in the rangeof 69 to 72 percent by weight.
 2. A pharmaceutical tablet systemaccording to claim 1, in which the voids are interstices between grainsof the powdered filler.
 3. A pharmaceutical tablet system according toclaim 2, in which the voids generally are sealed off from each other byvirtue of the hydrophobic material.
 4. A pharmaceutical tablet systemaccording to claim 1, in which the voids are micropores included withinthe hydrophobic material.
 5. A pharmaceutical tablet system according toclaim 1, in which the cup-shaped envelope is comprised of a mixture thatincludes at least one or more pharmaceutically active agents differentfrom said substances contained in one or more of the release layers. 6.A process of producing a pharmaceutical tablet system capable ofprolonged floating in or on gastric fluid for releasing therein one ormore pharmaceutically active substances in the course of an alternatesuccession of periods of substance release and no-release, saidalternate succession including at least two periods of substance releaseseparated by one period of no-release, whereby the tablet system is madeup of a multilayered core placed in a cup-shaped envelope, the core ismade up of release and no-release layers superposed in alternatesuccession to form a pile of layers that includes at least two releaselayers flanking an intermediate no-release layer, each release layerbeing composed of pharmaceutically acceptable excipient and/or carrierhaving admixed thereto at least one of said pharmaceutically activesubstances, each no-release layer being composed of pharmaceuticallyacceptable excipient and/or carrier devoid of said pharmaceuticallyactive substance, the cup-shaped envelope covers a bottom surface andside surfaces of the core placed therein while leaving exposed an uppersurface of the core, the cup-shaped envelope provides for buoyancy ofthe pharmaceutical tablet system with respect to gastric fluid by beingformed of a compression-sintered mixture with voids, the mixture beingcomprised by buoyancy-providing materials in the form of apharmaceutically acceptable hydrophobic material and pharmaceuticallyacceptable inert powdered filler, the hydrophobic material beingcomposed of fatty and/or waxy material capable of being sintered bycompression and whose bulk density is lower than gastric fluid density,and the powdered filler having a loose powder density that is lower thangastric fluid density, the powdered filler consisting of magnesiumaluminometasilicate; and the buoyancy-providing materials of thecup-shaped envelope being incorporated in the finished pharmaceuticaltablet system in the range of 69 to percent 72 by weight, the methodcomprising the steps of: coating the powdered filler with thehydrophobic material; granulating the resulting coated material; placinga layer of the resulting granulated material into a die; placing thecore onto the layer of granulated material within the die; forcing thecore into the layer of granulated material within the die; and removingthe resulting tablet system from the die.
 7. A process according toclaim 6, in which the step of forcing the core into the layer ofgranulated material within the die involves a compression of the tabletsystem made up of the cup-shaped envelope having the core insertedtherein to provide a snug fit between mutually facing bottom and sidesurfaces of the core and surface portions of the cup-shaped envelope. 8.A process of producing a cup-shaped envelope of a pharmaceutical tabletsystem involving the following steps: capable of prolonged floating inor on gastric fluid for releasing therein one or more pharmaceuticallyactive substances in the course of an alternate succession of periods ofsubstance release and no-release, said alternate succession including atleast two periods of substance release separated by one period ofno-release, whereby the tablet system is made up of a multilayered coreplaced in a cup-shaped envelope, the core is made up of release andno-release layers superposed in alternate succession to form a pile oflayers that includes at least two release layers flanking anintermediate no-release layer, each release layer being composed ofpharmaceutically acceptable excipient and/or carrier having admixedthereto at least one of said pharmaceutically active substances, eachno-release layer being composed of pharmaceutically acceptable excipientand/or carrier devoid of said pharmaceutically active substance, thecup-shaped envelope covers a bottom surface and side surfaces of thecore placed therein while leaving exposed an upper surface of the core,the cup-shaped envelope provides for buoyancy of the pharmaceuticaltablet system with respect to gastric fluid by being formed of acompression-sintered mixture with voids, the mixture being comprised bybuoyancy-providing materials in the form of a pharmaceuticallyacceptable hydrophobic material and pharmaceutically acceptable inertpowdered filler, the hydrophobic material being composed of fatty and/orwaxy material capable of being sintered by compression and whose bulkdensity is lower than gastric fluid density, and the powdered fillerhaving a loose powder density that is lower than gastric fluid density,the powdered filler consisting of magnesium aluminometasilicate; and thebuoyancy-providing materials of the cup-shaped envelope beingincorporated in the finished pharmaceutical tablet system in the rangeof 69 to 72 percent by weight, the method comprising: coating thepowdered filler with the hydrophobic material; granulating the resultingcoated material; placing a layer of the resulting granulated materialinto a die; forming the cup-shaped recess into the layer of granulatedmaterial by forcing a correspondingly shaped body into it within thedie; and removing the resulting cup-shaped envelope from the die.
 9. Aprocess according to claim 6, in which the step of coating the powderedfiller with the hydrophobic material comprises the step of spray-coatingperformed under vigorous stirring.
 10. A process according to claim 8,in which the step of coating the powdered filler with the hydrophobicmaterial comprises the step of spray-coating performed under vigorousstirring.
 11. A pharmaceutical tablet system according to claim 1,wherein said two periods of substance release separated by one period ofno-release comprise: a first release period being less than one hour; aperiod of no-release lasting longer than the first release period; and asecond release period having a prolonged duration.
 12. A pharmaceuticaltablet system according to claim 1, wherein said two periods ofsubstance release separated by one period of no-release comprise: afirst release period being less than one hour; a period of no-releaselasting longer than the first release period; and a second releaseperiod having a duration of less than one hour.